TEM imagen de Vibrio choleraeLa mayoría de la V. cholerae, la bacteria en el agua contaminada consumido por el anfitrión no sobrevivir a la acidez de las condiciones altamente estómago humano.[3] Las pocas bacterias que sobreviven conservar su energía y los nutrientes almacenados durante el paso por el estómago por el cierre de la producción de proteínas. Cuando las bacterias sobreviven salir del estómago y llegar al intestino delgado, que necesitan para impulsar a través de la espesa el moco que recubre el intestino delgado para llegar a la pared intestinal donde pueden prosperar. V. cholerae, bacteria iniciar la producción de la proteína cilíndrico hueco flagelina hacer flagelos, como las colas del látigo-rizado que girar para impulsarse a través de la mucosa del intestino delgado.Once the cholera bacteria reach the intestinal wall, they do not need the flagella propellers to move any longer. The bacteria stop producing the protein flagellin, thus again conserving energy and nutrients by changing the mix of proteins which they manufacture in response to the changed chemical surroundings. On reaching the intestinal wall, V. cholerae start producing the toxic proteins that give the infected person a watery diarrhea. This carries the multiplying new generations of V. cholerae bacteria out into the drinking water of the next host if proper sanitation measures are not in place.The cholera toxin (CTX or CT) is an oligomeric complex made up of six protein subunits: a single copy of the A subunit (part A), and five copies of the B subunit (part B), connected by a disulfide bond. The five B subunits form a five-membered ring that binds to GM1 gangliosides on the surface of the intestinal epithelium cells. The A1 portion of the A subunit is an enzyme that ADP-ribosylates G proteins, while the A2 chain fits into the central pore of the B subunit ring. Upon binding, the complex is taken into the cell via receptor-mediated endocytosis. Once inside the cell, the disulfide bond is reduced and the A1 subunit is freed to bind with a human partner protein called ADP-ribosylation factor 6 (Arf6).[4] Binding exposes its active site, allowing it to permanently ribosylate the Gs alpha subunit of the heterotrimeric G protein. This results in constitutive cAMP production, which in turn leads to secretion of H2O, Na+, K+, Cl−, and HCO3− into the lumen of the small intestine and rapid dehydration. The gene encoding the cholera toxin is introduced into V. cholerae by horizontal gene transfer. Virulent strains of V. cholerae carry a variant of lysogenic bacteriophage called CTXf or CTXφ.

Cholera Toxin. The delivery region (blue) binds membrane carbohydrates to get into cells. The toxic part (red) is activated inside the cell (PDB code: 1xtc).Microbiologists have studied the genetic mechanisms by which the V. cholerae bacteria turn off the production of some proteins and turn on the production of other proteins as they respond to the series of chemical environments they encounter, passing through the stomach, through the mucous layer of the small intestine, and on to the intestinal wall.[5] Of particular interest have been the genetic mechanisms by which cholera bacteria turn on the protein production of the toxins that interact with host cell mechanisms to pump chloride ions into the small intestine, creating an ionic pressure which prevents sodium ions from entering the cell. The chloride and sodium ions create a salt-water environment in the small intestines, which through osmosis can pull up to six liters of water per day through the intestinal cells, creating the massive amounts of diarrhea. The host can become rapidly dehydrated if an appropriate mixture of dilute salt water and sugar is not taken to replace the blood's water and salts lost in the diarrhea.By inserting separate, successive sections of V. cholerae DNA into the DNA of other bacteria such as E. coli that would not naturally produce the protein toxins, researchers have investigated the mechanisms by which V. cholerae responds to the changing chemical environments of the stomach, mucous layers, and intestinal wall. Researchers have discovered that there is a complex cascade of regulatory proteins that control expression of V. cholerae virulence determinants. In responding to the chemical environment at the intestinal wall, the V. cholerae bacteria produce the TcpP/TcpH proteins, which, together with the ToxR/ToxS proteins, activate the expression of the ToxT regulatory protein. ToxT then directly activates expression of virulence genes that produce the toxins that cause diarrhea in the infected person and that permit the bacteria to colonize the intestine.[5] Current research aims at discovering "the signal that makes the cholera bacteria stop swimming and start to colonize (that is, adhere to the cells of) the small intestine."[5][edit]Pathophysiology

[edit]SusceptibilityRecent epidemiologic research suggests that an individual's susceptibility to cholera (and other diarrhoeal infections) is affected by their blood type: those with type O blood are the most susceptible,[6][7] while those with type AB are the most resistant. Between these two extremes are the A and B blood types, with type A being more resistant than type B.[citation needed]About one million V. cholerae bacteria must typically be ingested to cause cholera in normally healthy adults, although increased susceptibility may be observed in those with a weakened immune system, individuals with decreased gastric acidity (as from the use of antacids), or those who are malnourished.It has also been hypothesized that the cystic fibrosis genetic mutation has been maintained in humans due to a selective advantage: heterozygous carriers of the mutation (who are thus not affected by cystic fibrosis) are more resistant to V. cholerae infections.[8] In this model, the genetic deficiency in the cystic fibrosis transmembrane conductance regulator channel proteins interferes with bacteria binding to the gastrointestinal epithelium, thus reducing the effects of an infection.[edit]Transmission

Drawing of Death bringing the cholera, in Le Petit JournalPeople infected with cholera suffer acute diarrhoea. This highly liquid diarrhoea, colloquially referred to as "rice-water stool," is loaded with bacteria that can infect water used by other people.[9] Cholera is transmitted through ingestion of water contaminated with the cholera bacterium, usually from feces or other effluent. The source of the contamination is typically other cholera patients when their untreated diarrhoea discharge is allowed to get into waterways or into groundwater or drinking water supplies. Any infected water and any foods washed in the water, as well as shellfish living in the affected waterway, can cause an infection. Cholera is rarely spread directly from person to person. V. cholerae harbours naturally in the zooplankton of fresh,[citation needed] brackish,[10] and salt water,[10] attached primarily to their chitinous exoskeleton.[11] Both toxic and non-toxic strains exist. Non-toxic strains can acquire toxicity through a lysogenic bacteriophage.[12] Coastal cholera outbreaks typically follow zooplankton blooms, thus making cholera a zoonotic disease.[edit]Human contribution to transmissibilityCholera bacteria grown in vitro encounter difficulty subsequently growing in humans without additional stomach acid buffering. In a 2002 study at Tufts University School of Medicine, it was found that stomach acidity is a principal agent that advances epidemic spread.[13] In their findings, the researchers found that human colonization creates a hyperinfectious bacterial state that is maintained after dissemination and that may contribute to epidemic spread of the disease. When these hyperinfectious bacteria underwent transcription profiles, they were found to possess a unique physiological and behavioural state, characterized by high expression levels of genes required for nutrient acquisition and motility, and low expression levels of genes required for bacterial chemotaxis. Thus, the spread of cholera can be expedited by host physiology.[edit]Diagnosis

In epidemic situations, a clinical diagnosis is made by taking a history of symptoms from the patient and by a brief examination only. Treatment is usually started without or before confirmation by laboratory analysis of specimens.Stool and swab samples collected in the acute stage of the disease, before antibiotics have been administered, are the most useful specimens for laboratory diagnosis. If an epidemic of cholera is suspected, the most common causative agent is Vibrio cholerae O1. If V. cholerae serogroup O1 is not isolated, the laboratory should test for V. cholerae O139. However, if neither of these organisms is isolated, it is necessary to send stool specimens to a reference laboratory. Infection with V. cholerae O139 should be reported and handled in the same manner as that caused by V. cholerae O1. The associated diarrheal illness should be referred to as cholera and must be reported.[14]A number of special media have been employed for the cultivation for cholera vibrios. They are classified as follows:[edit]Enrichment mediaAlkaline peptone water at pH 8.6Monsur's taurocholate tellurite peptone water at pH 9.2[edit]Plating mediaAlkaline bile salt agar (BSA): The colonies are very similar to those on nutrient agar.Monsur's gelatin Tauro cholate trypticase tellurite agar (GTTA) medium: Cholera vibrios produce small translucent colonies with a greyish black centre.TCBS medium: This the mostly widely used medium. This medium contains thiosulphate, citrate, bile salts and sucrose. Cholera vibrios produce flat 2–3 mm in diameter, yellow nucleated colonies.Direct microscopy of stool is not recommended as it is unreliable. Microscopy is preferred only after enrichment, as this process reveals the characteristic motility of Vibrios and its inhibition by appropriate antiserum. Diagnosis can be confirmed as well as serotyping done by agglutination with specific sera.[edit]Prevention

Cholera hospital in Dhaka, showing typical cholera beds.Although cholera may be life-threatening, prevention of the disease is normally straightforward if proper sanitation practices are followed. In developed countries, due to nearly universal advanced water treatment and sanitation practices, cholera is no longer a major health threat. The last major outbreak of cholera in the United States occurred in 1910-1911.[15][16] Travellers should be aware of how the disease is transmitted and what can be done to prevent it. Effective sanitation practices, if instituted and adhered to in time, are usually sufficient to stop an epidemic. There are several points along the cholera transmission path at which its spread may be (and should be) halted:Sterilization: Proper disposal and treatment of infected faecal waste water produced by cholera victims and all contaminated materials (e.g. clothing, bedding, etc.) is essential. All materials that come in contact with cholera patients should be sterilized by washing in hot water using chlorine bleach if possible. Hands that touch cholera patients or their clothing, bedding, etc., should be thoroughly cleaned and disinfected with chlorinated water or other effective anti-microbial agents.Sewage: anti-bacterial treatment of general sewage by chlorine, ozone, ultra-violet light or other effective treatment before it enters the waterways or underground water supplies helps prevent undiagnosed patients from inadvertently spreading the disease.Sources: Warnings about possible cholera contamination should be posted around contaminated water sources with directions on how to decontaminate the water (boiling, chlorination etc.) for possible use.Water purification: All water used for drinking, washing, or cooking should be sterilized by either boiling, chlorination, ozone water treatment, ultra-violet light sterilization (e.g. by solar water disinfection), or anti-microbial filtration in any area where cholera may be present. Chlorination and boiling are often the least expensive and most effective means of halting transmission. Cloth filters, though very basic, have significantly reduced the occurrence of cholera when used in poor villages in Bangladesh that rely on untreated surface water. Better anti-microbial filters like those present in advanced individual water treatment hiking kits are most effective. Public health education and adherence to appropriate sanitation practices are of primary importance to help prevent and control transmission of cholera and other diseases.A vaccine for cholera is available in some countries, but prophylactic usage is not currently recommended by the Centres for Disease Control and Prevention (CDC) for most travelers.[17] During recent years, substantial progress has been made in developing new oral vaccines against cholera. Two oral cholera vaccines, which have been evaluated with volunteers from industrialized countries and in regions with endemic cholera, are commercially available in several countries: a killed whole-cell V. cholerae O1 in combination with purified recombinant B subunit of cholera toxin and a live-attenuated live oral cholera vaccine, containing the genetically manipulated V. cholerae O1 strain CVD 103-HgR. The appearance of V. cholerae O139 has influenced efforts in order to develop an effective and practical cholera vaccine since none of the currently available vaccines is effective against this strain.[14] The newer vaccine (brand name: Dukoral), an orally administered inactivated whole cell vaccine, appears to provide somewhat better immunity and have fewer adverse effects than the previously available vaccine.[17] This safe and effective vaccine is available for use by individuals and health personnel. Work is under way to investigate the role of mass vaccination.[18]Sensitive surveillance and prompt reporting allow for containing cholera epidemics rapidly. Cholera exists as a seasonal disease in many endemic countries, occurring annually mostly during rainy seasons. Surveillance systems can provide early alerts to outbreaks, therefore leading to coordinated response and assist in preparation of preparedness plans. Efficient surveillance systems can also improve the risk assessment for potential cholera outbreaks. Understanding the seasonality and location of outbreaks provide guidance for improving cholera control activities for the most vulnerable. This will also aid in the developing indicators for appropriate use of oral cholera vaccine.[19][edit]Treatment

Cholera patient being treated by medical staff in 1992.In most cases cholera can be successfully treated with oral rehydration therapy (ORT). ORT is highly effective, safe, and simple to administer: prompt replacement of water and electrolytes is the principal treatment for cholera, as dehydration and electrolyte depletion occur rapidly. In situations where commercially produced ORT sachets are too expensive or difficult to obtain, alternative homemade solutions using various formulas of water, sugar, table salt, baking soda, and fruit offer less expensive methods of electrolyte repletion. In severe cholera cases with significant dehydration, the administration of intravenous rehydration solutions may be necessary.Antibiotics shorten the course of the disease and reduce the severity of the symptoms; however, oral rehydration therapy remains the principal treatment. Tetracycline is typically used as the primary antibiotic, although some strains of V. cholerae have shown resistance. Other antibiotics that have been proven effective against V. cholerae include cotrimoxazole, erythromycin, doxycycline, chloramphenicol, and furazolidone.[20] Fluoroquinolones such as norfloxacin also may be used, but resistance has been reported.[21]Rapid diagnostic assay methods are available for the identification of multi-drug resistant V. cholerae.[22] New generation antimicrobials have been discovered which are effective against V. cholerae in in vitro studies.[23]The success of treatment is significantly affected by the speed and method of treatment. If cholera patients are treated quickly and properly, the mortality rate is less than 1%; however, with untreated cholera, the mortality rate rises to 50–60%.[24][25][edit]Epidemiology

Although much is known about the mechanisms behind the spread of cholera, this has not led to a full understanding of what makes cholera outbreaks happen some places and not others. Lack of treatment of human feces and lack of treatment of drinking water greatly facilitate its spread, but bodies of water can serve as a reservoir and seafood shipped long distances can spread the disease. Cholera was not known in the Americas for most of the 20th century, but it reappeared towards the end of that century and seems likely to persist.[26][edit]Sample outbreaks

By 12 February 2009, the number of cases of infection by cholera in sub-Saharan Africa had reached 128,548 and the number of fatalities, 4,053.In 2000, some 140,000 cholera cases were officially notified to WHO. Africa accounted for 87% of these cases.[27]July - December 2007 - A lack of clean drinking water in Iraq has led to an outbreak of cholera.[28] As of 2 December 2007, the UN has reported 22 deaths and 4,569 laboratory-confirmed cases.[29]August 2007 - The cholera epidemic started in Orissa, India. The outbreak has affected Rayagada, Koraput and Kalahandi districts where more than 2,000 people have been admitted to hospitals.[30]August - October 2008 - As of 29 October 2008, a total of 644 laboratory-confirmed cholera cases, including eight deaths, had been verified in Iraq.[31]March - April 2008 - 2,490 people from 20 provinces throughout Vietnam have been hospitalized with acute diarrhea. Of those hospitalized, 377 patients tested positive for cholera.[32]November 2008 - Doctors Without Borders reported an outbreak in a refugee camp in the Democratic Republic of the Congo's eastern provincial capital of Goma. Some 45 cases were reportedly treated between November 7 through 9th.August 2008 - April 2009: In the 2008 Zimbabwean cholera outbreak, which is still continuing, an estimated 96,591 people in the country have been infected with cholera and, by 16 April 2009, 4,201 deaths had been reported.[33] According to the World Health Organization, during the week of 22–28 March 2009, the "Crude Case Fatality Ratio (CFR)" had dropped from 4.2% to 3.7%.[33] The daily updates for the period 29 March 2009 to 7 April 2009, list 1748 cases and 64 fatalities, giving a weekly CFR of 3.66% (see table above);[34] however, those for the period 8 April to 16 April list 1375 new cases and 62 deaths (and a resulting CFR of 4.5%).[34] The CFR had remained above 4.7% for most of January and early February 2009.[35]January 2009 - The Mpumalanga province of South Africa has confirmed over 381 new cases of Cholera, bringing the total number of cases treated since November 2008 to 2276. 19 people have died in the province since the outbreak.[36]August 2010 - Nigeria is reaching epidemic proportions after wide spread confirmation of the Cholera outbreaks in 12 of its 36 states. 6400 cases have been reported with 352 reported deaths. The health ministry blamed the outbreak on heavy seasonal rainfall and poor sanitation.[37]October 2010 - Outbreak in in the rural Artibonite region of Haiti, killing at least 250 and infecting more than 3,000. The outbreak has been attributed to widespread homelessness following the 2010 Haiti earthquake, forcing people to drink from the local rivers.[38][edit]Pandemic genetic diversityAmplified fragment length polymorphism (AFLP) fingerprinting of the pandemic isolates of Vibrio cholerae has revealed variation in the genetic structure. Two clusters have been identified: Cluster I and Cluster II. For the most part Cluster I consists of strains from the 1960s and 1970s, while Cluster II largely contains strains from the 1980s and 1990s, based on the change in the clone structure. This grouping of strains is best seen in the strains from the African Continent.[39][edit]History

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